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FRCPath > Molecular Genetics > Flashcards

Molecular Genetics Flashcards

1
Q

Name 2 X-Linked Recessive disorders

A

Duchenne/Becker Muscular Dystrophy
SBMA
Androgen Insensitivity Syndrome

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2
Q

Name 2 X-Linked Dominant disorders

A

X-linked hypophosphatemia
X-linked Alport Syndrome
Rett Syndrome

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3
Q

Name three clinical features associated with CF

A

Chronic coughing and wheezing
Failure to thrive
Pancreatic insufficiency

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4
Q

Name the most common CF mutation

A

p.Phe508del - 75%

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5
Q

Describe the function of CFTR (7q31.2)

A

Cyclic AMP-activated chloride channel located in the plasma membrane of secretory eithelial cells

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6
Q

How many types of SMA are there?

A

6 - Prenatal, type 1, Type 2, Type 3, Type 4 and atypical SMA

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7
Q

Describe 3 characteristic features of SMA

A

Progressive proximal symmetrical limb and trunk muscle weakness,
Intercostal muscle weakness,
Fine tremor
Facial weakness

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8
Q

What is the most common type of SMA? Describe

A

Type 1 - profound hypotonia, symmetrical flaccid paralysis, progressive, death at early age

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9
Q

Give me some molecular facts about SMA

A

SMN1 and pseudogene SMN2
4% population have 2 copies of SMN1 on one chrm (range 0-5)
95-98% SMA homozygous for deletion of at least exon 7
2-5% are compound heterozygotes for del and pathogenic inactivating mutn

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10
Q

How do we interpret SMA carrier testing?

A

Bayes calculation

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11
Q

Briefly describe CRISPR-Cas9

A

Gene editing - Cas9 protein complex containing specific sequence of RNA - once complimentary sequence is identified the DNA is cut and released into the cell. Cellular DNA repair mechanisms repair the break - but this is prone to error. By introducing templates of ‘corrected’ DNA - these specific sequences can be incorporated to replace mutant alleles

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12
Q

What is the clinical significance of 36-39 CAG repeats in Huntington Disease?

A

Reduced penetrance - may or may not be affected

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13
Q

Above what number of CAG repeats would you see fully penetrant development of Huntington Disease?

A

40 CAG repeats

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14
Q

What is the significance of 27-35 CAG repeats in Huntington Disease?

A

Intermediate allele - will not cause disease but may expand to cause disease if paternally transmitted

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15
Q

Name 3 disorders associated with FMR1

A

Fragile X, FXTAS and POI

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16
Q

How is Fragile X caused?

A

Expansion of unstable 5’ UTR CGG repeat to >200 repeats, causing gene silencing

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17
Q

Give 3 clinical features of Fragile X in males

A

moderate/severe intellectual and social impairment, characteristic facial features, joint laxity, macro-orchidism

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18
Q

Give the clinical presentation of Fragile X in females

A

Variable phenotype - apparently normal approx 50%) through to mild/moderate mental and social impairment

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19
Q

What is the significance of repeat size of 55-200 in FMR1?

A

Premutation - may expand in maternal line to cause FraX in future generations. Patients may develop FXTAS or POI

20
Q

What is the proposed disease mechanism for FXTAS/POI

A

NOT the same as FraX - ?toxic gain of function?

21
Q

What is the location of FMR1?

A

Xq27.3

22
Q

What is the role of FMRP protein?

A

RNA binding protein, present in many tissues including brain, ovaries and testes - thought to act as a shuttle within cells by transporting mRNA from nucleus to areas of cell where proteins assembled. Also helps to control when the instructions in these mRNA molecules are used to build proteins.

23
Q

Name 2 NGS platforms

A

Agilent Sure Select, ThermoFisher Ion Torrent, Illumina HiSeq/MiSeq SBS

24
Q

What are the mutation ranges for SBMA?

A 
Normal - 34 CAG repeats or less
Questionable - 35 CAG repeats
Reduced penetrance - 36-37 CAG repeats
Affected fully penetrant - 38 CAG repeats or greater
Sequence any 35-37 repeats
25
Q

Name 3 CAG expansion disorders

A

Huntingtons
SBMA
SCAs - 7 of them

26
Q

Name 2 CGG expansion disorders

A

Fragile X

FXTAS

27
Q

Name 3 CTG expansion disorders

A

Myotonic Dystrophy 1
Huntington Like Disease 2
SCA 8

28
Q

Name a GAA expansion disorder

A

Friedreich Ataxia

29
Q

Name a CCTG expansion disorder

A

Myotonic Dystrophy 2

29
Q

What additional features might you see in a juvenile HD patient with a large expansion?

A

Bradykinesia

Dystonia

30
Q

What factors can contribute to pathogenic mechanism of repeat expansion diseases

A 
Sequence of repeat
Size of repeat
Location of repeat within gene
Whether repeat encodes RNA or protein
Function of repeat-containing gene
Extent of meiosis and somatic instability
31
Q

What causes Myotonic Dystrophy 1?

A

CTG expansion in the 3’UTR of the DMPK gene

32
Q

What causes Myotonic Dystrophy 2?

A

CCTG repeat in intron 1 of the CNBP gene

33
Q

What are some clinical features of DM1?

A 
Progressive weakness and myotonia
Cataracts
Cardiac arrhythmias
Endocrinopathy
Cognitive impairment
34
Q

Name 7 methods for detecting UPD

A 
MS-PCR
MS-Melt Curve Analysis
MS-Pyrosequencing
Microsatellite analysis
MS-MLPA
SNP Arrays
WGS/WES - trios especially powerful
35
Q

Name 3 methods of detecting UPD that rely on bisulphite conversion

A

MS-PCR
MS-Melt Curve Analysis
MS-Pyrosequencing

36
Q

What are the pros and cons of using microsatellite analysis for UPD detection?

A

Pros: Will distinguish whole/partial UPD and Hetero/Isodisomy, relatively cheap, no prior conversion step, reliable method
Cons: Need parental samples and informative markers

37
Q

Describe MS-MLPA

A

2 tubes, 1 for CNV, 1 for methylation specific enzyme digest. Methylated DNA won’t digest, and then will amplify during MLPA.
Semi quantitative, no parental bloods need, can distinguish UPD from deletion from a small amount of DNA.
No need for parental samples, can’t distinguish UPD and mutation in imprinting centre

38
Q

How can you use WGS/WES for detection of UPD?

A

Trio analysis - bioinformatic pipelines will check for identity by looking for biparental inheritance
Can detect mosaics and can distinguish full range of del/UPD/IC defect
Expensive and time consuming, requires parental samples

39
Q

What are the pros and cons of using bisulphite conversion for UPD testing?

A

Allows for analysis without parental samples, bisulphite conversion kits readily available, cheap and effective
Won’t distinguish segmental/whole UPD, or del from UPD (MS-PCR)

40
Q

Describe Class 1 CFTR mutations

A

Nonsense, most frameshift mutns and large del’s create premature stop codons causing defective protein synthesis and no CFTR protein expressed. Severe phenotype, W128X, R553X, G542X. Treatments - readthrough drugs - Ataluren phase 3 trials

41
Q

Describe Class 2 CFTR mutations

A

Some missense mutns and in frame del’s disrupt CFTR protein folding and trafficking to the surface. F506del, N1303K. Treatments: correctors to promote folding - Lumacafter

42
Q

Describe Class 3 CFTR mutations

A

Some missense mutns result in substitution of aa’s, disrupting regulation of CFTR channel, which no longer opens in response to channel agonists. G551D, G551S, G1349D. Treatment Ivacafter being trialled.

43
Q

Describe Class 4 CFTR mutations

A

Some missense mutations result in changes to CFTR protein structure that forms the pore of the channel which can restrict the movement of Cl- ions through the channel - conductance defect. Eg R117H, R334W, R347P. Ivacafter being trialled.

44
Q

Describe Class 5 CFTR mutations

A

Some missense mutations result in alternative splicing that disrupts mRNA processing - extremely reduced amounts of normal CFTR protein are synthesised, less protein at cell surface. 2789+5G>A, A455E. Treatments are focussed on compounds that enhance CFTR retention/anchoring

45
Q

Describe Class 6 CFTR mutations

A

Different types of mutations increase the turnover of CFTR protein at the cell surface, quickly removed and degraded by cell machinery. Egs include Rescued F508del, 120del23, N287Y, 4326delTC, 4279insA

46
Q

How many classes of CFTR mutations are there?

A

6

FRCPath (9 decks)

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